Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent disease of the nails, skin, oral and genital mucosae. The pathogenesis of CMC disease (CMCD), a genetic form of CMC, has long remained elusive. Our identification of autosomal recessive (AR) IL-17RA and autosomal dominant (AD) IL-17F deficiencies paved the way for the identification of germ line mutations in the coiled-coil domain (CCD) of STAT1 in AD CMCD kindreds. We further showed that (i) the mutations were gain-of-function (GOF), enhancing STAT1- dependent cellular responses to cytokines, including IL-27 and IFNs in particular, and that (ii) CMC resulted from impaired development of IL-17 T cells. We had previously reported loss-of-function (LOF) mutations in STAT1 in patients with other infections, including mycobacterial and viral diseases. Astoundingly, STAT1 is the first human gene whose allelic diversity governs distinct infectious diseases. The molecular, immunological, and clinical features of patients with GOF STAT1 mutations however remain largely unknown. At the molecular level, we intend to describe the allelic diversity of GOF alleles and decipher the mechanism by which these various missense mutations of STAT1 are GOF. At the immunological level, we will test whether STAT1-dependent cytokines, such as IFNs and IL-27, impair the development of IL-17 T cells in vivo and in vitro, in both healthy controls and patients with GOF mutations. At the clinical level, we will thoroughly describe the clinical features of 25 American patients with CMCD sharing GOF STAT1 mutations, focusing in particular on phenotypes other than CMC, taking advantage of the capacity of the NIH Clinical Center. Overall, the molecular, immunological, and clinical features unraveled in this study will be integrated in order to define the causal relationships that determine the pathogenesis of CMC and other immunological and clinical phenotypes in patients with GOF STAT1 mutations. We have pioneered the human genetic dissection of inborn errors of both IL-17 and STAT1. We have already diagnosed 105 patients world-wide with GOF STAT1 mutations. We have shown that nearly a third of the mutations affect regions other than the CCD yet that all GOF mutations impair nuclear dephosphorylation of STAT1. We have also shown that IL-27 and IFNs inhibit the in vitro development of IL-17 T cells in patients with GOF STAT1 mutations, whereas antibodies against these cytokines rescue this phenotype. Finally, we have observed that many patients display features other than CMC, including auto-immunity, cerebral aneurysms, cancer, invasive fungal disease, and herpes virus reactivation. These preliminary data neatly illustrate the validit of our hypotheses, the power of our collaborative approach, and the potential of our integrated research. Our project is highly innovative, yet supported by strong preliminary evidence. This collaborative research will characterize the molecular, immunological, and clinical features of a unique human condition. The in-depth and integrated investigation of cells and patients with GOF STAT1 mutations has far- reaching and broad biological and clinical implications, for various physiological and pathological processes.